Research Interests

My early work addressed the role of oxidative stress signaling events, UPS dysfunction and apoptotic mechanisms in dopaminergic neurotoxicant-induced cellular injury. Recently, our lab has focused on understanding the molecular mechanisms by which PKCδ regulates the apoptotic cell signaling cascade following exposure to dopaminergic neurotoxicants. We discovered that mitochondria-mediated oxidative stress signaling events in conjunction with the caspase-3-mediated cell death signaling cascade contribute to the demise of dopaminergic neuronal cells via the activation of PKCδ. Moreover, we demonstrated the functional cross-talk between histone hyperacetylation and PKCδ upregulation in dopaminergic neuronal cell death in experimental models of PD, thus emphasizing the central role of PKCδ in dopaminergic neuronal injury. I served as the primary investigator or Co-I in these studies.

During the last several years, we have also studied the role of microglial activation in dopaminergic neuronal injury. In this context, we demonstrated that proteolytic activation of PKCδ serves as a key downstream mediator of TNF-α-induced dopaminergic neuronal injury and that attenuation of PKCδ activation affords protection against inflammasome-induced dopaminergic neuronal injury. Additionally, we also developed a high-yielding magnetic separation methodology for the isolation of primary microglia. Recently, we showed that Fyn kinase, a non-receptor tyrosine kinase in conjunction with PKCδ is a critical regulator of microglia reactive like activation state in nigral DAergic neurodegeneration in experimental models of PD. Our findings have important clinical implications for the treatment of neuroinflammation related disorders including PD.

My group has also made several important discoveries concerning the investigation of cellular and molecular mechanisms underlying drugs of abuse-induced neurotoxicity such as methamphetamine (MA). We demonstrated that a redox sensitive kinase dependent induction of autophagy might be critically linked to MA-induced DAergic neurotoxicity. Using in vitro and in vivo models, we showed that autophagy might represent a key neuroprotective mechanism that limited MA-induced apoptotic cell death by modulating PKC delta-dependent mitochondria-mediated oxidative stress dependent signaling events. Further research highlighted the pivotal contribution of GSH redox status in regulating the functional interplay between autophagy and apoptosis in drug-induced dopaminergic neuronal loss. Similarly, our work demonstrated the role of autophagy in Mn nanoparticle and pesticide-induced apoptotic cell death. I served as the primary investigator or Co-I in these studies.